Sterility Requirements for Inhalation Solution Products

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 200

[Docket No. 96N-0048]

Sterility Requirements for Inhalation Solution Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

its regulations to require that all inhalation solutions for

nebulization be sterile. Inhalation solutions for nebulization, as the

term is used in this document, refers to inhalation solutions

administered as a fine aqueous mist created by an atomizer or

nebulizer. Currently, approximately half of these products are

manufactured to be sterile. Based on reports of adverse drug

experiences from contaminated nonsterile inhalation solutions for

nebulization and recalls of these products, FDA is taking this action

to ensure the safety and effectiveness of these solutions.

DATES: Written comments by December 22, 1997. Submit written comments

on the information collection requirements by October 23, 1997. FDA

proposes that any final rule that may issue based on this proposal

become effective March 23, 1998.

ADDRESSES: Submit written comments on this proposed rule to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 12420

Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on

the information collection requirements to the Office of Information

and Regulatory Affairs, Office of Management and Budget (OMB), New

Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC

20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Carol E. Drew, Center for Drug

Evaluation and Research (HFD-7), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

Inhalation solutions for nebulization are used to treat a variety

of breathing disorders. Currently, approximately half of the marketed

products are manufactured to be sterile. Those products not

manufactured to be sterile are often manufactured under assigned

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microbial count limits. For the reasons stated below, FDA has

determined that current manufacturing methods and purported safeguards

against contamination, including the microbial limits test, have not

prevented dangerous microbial contamination of nonsterile inhalation

solutions for nebulization. A sterility requirement is needed to

prevent such microbial contamination.

Contaminated inhalation solutions for nebulization are likely to

cause lung infections because the drug product is introduced directly

into the lungs in a manner which at least partially bypasses the

patient's natural defense mechanisms. Many patients using inhalation

solution products for nebulization have chronic obstructive airway

disease or cystic fibrosis, or are immunocompromised. Microbial

contamination of these products may result in serious health

consequences due to opportunistic pathogens entering the lungs or to

the possible inactivation of the drug product by these microorganisms.

Based on the significant health risk to users, FDA is proposing to

require that all aqueous-based inhalation solutions for nebulization be

manufactured as sterile.

Contamination problems with several different inhalation solution

products and numerous adverse experience reports have led to FDA's

determination that a sterility requirement is necessary for these

products. In January 1994, a marketed albuterol sulfate inhalation

solution product was found to be contaminated with a bacterium best

identified as belonging to the Pseudomonas fluorescens/putida group.

The manufacturer voluntarily recalled the product (class I recall to

the consumer level) and issued a press release regarding the recall.

In June 1992, a manufacturer recalled its metaproterenol sulfate

inhalation solution for nebulization when the product was found to

contain excessive microbial growth identified as P. gladioli/cepacia. A

press release was also issued concerning this recall.

In 1987, an FDA investigator identified at least two potential

human fungal pathogens (Aspergillus glaucus and Chrysosporium) in

another albuterol sulfate inhalation solution for nebulization before

market distribution.

A sterility requirement for all inhalation solutions for

nebulization will provide the necessary assurance that these solutions

will not be contaminated. The sterility requirement is necessary for

several reasons.

First, there is a high risk of contamination of inhalation

solutions. Microbial contaminants identified in two of the recalls were

Pseudomonas species (spp.), which are ubiquitous and are commonly found

in pharmaceutical water supplies and nonsterile manufacturing

environments.

Second, most species of Pseudomonas associated with the

contamination of inhalation solutions have the potential to be human

pathogens. Of special concern is the fact that many of the patients

using these products have compromised pulmonary defense mechanisms and

are therefore at a particularly high risk of serious infection.

Third, adherence to current good manufacturing practice (CGMP)

regulations without appropriate sterilization procedures does not

provide an adequate level of assurance that inhalation solutions for

nebulization will not be contaminated. Even if antimicrobial

preservatives are used in a product, they may not be effective because

many bacteria, including Pseudomonas spp., may develop resistance to

these preservatives. The albuterol sulfate product recalled in January

1994, for example, contained benzalkonium chloride, an antimicrobial

preservative, yet the preservative failed to prevent microbial

contamination of the product. Resistance to preservatives is not

species specific; strains of many species are resistant. Furthermore,

use of a single preservative in the manufacture of a nonsterile

inhalation solution for an extended period may actually select for

preservative-resistant strains of Pseudomonas spp. or other bacteria.

Also, the microbial limits test does not ensure against

contamination. End-product microbial limits tests performed prior to

distribution may not be capable of detecting sufficiently low levels of

contamination; a product that initially passes the microbial limits

test may support the growth of contaminating organisms, which could

later grow to unacceptable levels.

FDA has therefore determined that all inhalation solutions for

nebulization should be manufactured as sterile products. Any failure to

comply with the sterility requirement would result in a finding that

the drug product is adulterated under section 501(a)(2)(B) of the

Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.

351(a)(2)(B)), and misbranded under section 502(j) of the act (21

U.S.C. 352(j)). Failure to comply with the sterility requirement would

also result in the agency's refusal to approve a new or abbreviated

application for the product, pursuant to section 505(d)(1), (d)(2),

(d)(3), and (j)(3)(A) of the act (21 U.S.C. 355(d)(1), (d)(2), (d)(3),

and (j)(3)(A)).

II. Description of the Proposed Regulation

This proposal would amend the regulations governing requirements

for specific classes of drugs to include new Sec. 200.51 for inhalation

solutions for nebulization. Proposed Sec. 200.51(a) would require that

all prescription and over-the-counter (OTC) inhalation solutions for

nebulization be sterile. Manufacturers may use any appropriate process

to achieve sterility of their inhalation solution products, as long as

the method is in compliance with current FDA regulations. In the

Federal Register of October 11, 1991 (56 FR 51354), FDA proposed to

require that manufacturers use a terminal sterilization process when

preparing a sterile drug unless the process adversely affects the drug

product. The October 11, 1991, proposed rule would require that

manufacturers include in their applications a written justification for

not using terminal sterilization if such process is not appropriate.

Should that proposed rule become final, manufacturers of inhalation

solution products would be subject to its requirements.

Under this proposal, all manufacturers of nonsterile inhalation

solutions for nebulization have until 1 year after the date of

publication of the final rule to comply with the sterility requirement.

This effective date reflects the time that FDA believes applicants may

need to establish the sterility of their products.

Persons holding an approved application for a nonsterile inhalation

solution product should submit to FDA a supplemental application

establishing the sterility of the product. If they intend to sterilize

their product by terminal sterilization or make other changes listed

under Sec. 314.70(b)(2) (21 CFR 314.70(b)(2)), they must obtain FDA

approval of a supplement under that section before making the

change(s). If they intend to manufacture the sterile product by aseptic

processing, to retain the same container and closure system, and make

no changes other than those listed under Sec. 314.70(c)(1), they may

submit a supplemental application under that section.

The following information should be included in the supplements:

Complete qualification data for the aseptic process, executed batch

record for a production batch of the product using the approved

formulation, in-process and release control data, updated release

specifications that include sterility, 3 months' accelerated stability

data, updated stability protocol to

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include either sterility or container/closure integrity testing

initially and at expiry, and commitment to place the first three

commercial batches into the routine stability program and submit the

data in annual reports.

Proposed Sec. 200.51(b) states that manufacturers must comply with

the recordkeeping requirements of 21 CFR 211.113(b) of FDA's CGMP

regulations. This section requires that manufacturers establish and

follow appropriate written procedures designed to prevent

microbiological contamination of drug products purporting to be

sterile. Such procedures must include validation of any sterilization

process.

III. Proposed Effective Date

The agency's proposal would prohibit all manufacturers of

nonsterile inhalation solution products for nebulization, including

those products currently approved, from introducing or delivering for

introduction into interstate commerce any such products that are

nonsterile from 1 year after the date of publication in the Federal

Register of any final rule based on this proposal.

Holders of approved new drug applications (NDA's) and abbreviated

new drug applications (ANDA's) must submit data to FDA to establish

sterility of these products within 1 year after the publication in the

Federal Register of any final rule based on this proposal. This

effective date reflects the time that FDA believes applicants may need

to establish the sterility of their products.

Any NDA or ANDA for a nonsterile inhalation solution for

nebulization under review by FDA on or after the date of publication of

the final rule but before the effective date of the final rule may be

approved if the application is otherwise approvable and the applicant

agrees to establish the sterility of its product by the effective date.

On or after the effective date of the final rule, FDA will refuse to

approve an NDA or ANDA for a nonsterile inhalation solution for

nebulization if the applicant has not established the sterility of the

product.

IV. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action

is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

V. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),

and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive

Order 12866 directs agencies to assess all costs and benefits of

available regulatory alternatives and, when regulation is necessary, to

select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Unless an agency

certifies that a rule will not have a significant economic impact on a

substantial number of small entities, the Regulatory Flexibility Act

requires an analysis of regulatory options that would minimize any

significant impact of a rule on small entities. The Unfunded Mandates

Reform Act requires that agencies prepare an assessment of anticipated

costs and benefits before proposing any rule that may result in an

annual expenditure by State, local, and tribal governments, in the

aggregate, or by the private sector, of $100,000,000 (adjusted annually

for inflation).

The expected aggregate costs of this proposed rule, and the

anticipated impact of the rule on small entities, are described in the

analysis below. The agency believes that the proposed rule is

consistent with the regulatory philosophy and principles identified in

the Executive Order. This rule is not a significant regulatory action

as defined by the Executive Order, does not impose any mandates on

State, local, or tribal governments, and is not a significant

regulatory action under the Unfunded Mandates Reform Act. Based on the

following analysis, FDA estimates that this rule will have significant

adverse effects on about four to five small firms that currently

manufacture nonsterile inhalation solutions for nebulization. However,

since the exact number of firms manufacturing nonsterile inhalation

solutions is not certain, FDA invites comments from firms that believe

they would be affected by the proposed rule. The statutory basis for

FDA's authority to issue the rule is presented previously in this

preamble. FDA has not identified any other Federal rules that

duplicate, overlap, or conflict with the proposed rule.

As described in section I of this document, the objective of the

proposed rule is to ensure that all inhalation solutions for

nebulization are manufactured as sterile products and are thus safe and

effective for use. Nonsterile inhalation solutions have been found to

result in serious health consequences to users. By ensuring

sterilization, the proposed rule is expected to yield benefits from the

elimination of extended patient suffering and hospitalization

associated with contaminated nonsterile inhalation solution products.

In addition, the industry would benefit by avoiding liability claims

from persons harmed due to the contamination of nonsterile inhalation

solution products.

A. Affected Entities

This proposed rule would affect only those manufacturers of

inhalation solutions for nebulization that do not already manufacture

the products to be sterile. Based on its compliance data base, FDA

believes that all innovator prescription products are currently

manufactured as sterile. Of the approximately 28 generic and OTC firms

that manufacture inhalation solutions, FDA estimates that up to five

firms may still use nonsterile manufacturing processes and will be

affected by this proposed rule. (The remainder are believed to have

either implemented sterile processes themselves or to have contracted

out the manufacturing of their inhalation products to firms that use a

sterile process.) All of these affected firms may be small entities as

defined by the Regulatory Flexibility Act.

B. Compliance Requirements and Costs

To comply with this rule, the affected firms must implement a

sterile process for manufacturing their inhalation products, either by

converting their in-house manufacturing operations to ensure that the

products are sterile, or by arranging to have these products

manufactured under contract by a firm that can do so under sterile

conditions. In addition, affected firms must: (1) Develop appropriate

written procedures designed to prevent contamination of the products,

including validation of the new inhalation solution processes; and (2)

submit to FDA a supplemental application establishing the sterility of

the product.

Firms choosing to convert in-house manufacturing operations would

need to set up an in-plant sterilization process by constructing a

clean room especially designated for the inhalation solution product.

FDA finds that the cost of building a new clean room may amount to

almost $600 per square foot. The size of pharmaceutical clean rooms is

reported to vary widely, from 200 to 2,500 square feet. Thus, the

estimated cost of installing a clean room in a manufacturing facility

may range from $120,000 to $1,500,000 per firm. Since affected firms

would presumably contract out their manufacturing process if to do so

would lower their costs of

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complying with this proposed rule, this figure is an upper bound.

Firms would also need to validate the new inhalation solution

processes at an estimated cost of $75,000 to $100,000 per product. The

firms that would need to complete these validation procedures produce

an average of approximately two inhalation products each, leading to

validation costs per firm of approximately $150,000 to $200,000. Each

firm would also be required to incur the paperwork costs associated

with filing a supplemental application for each product with FDA.

Thus, overall costs for implementing and validating a sterile

manufacturing process for inhalation products would total approximately

$270,000 to $1,700,000 per affected firm. Assuming that five firms are

affected, the costs of complying with this rule would range from

approximately $1,350,000 to $8,500,000. Amortized over 10 years at a 7

percent interest rate implies total annualized costs of $192,000 to

$1,210,000. In addition, affected firms will incur any costs associated

with preparing and submitting a supplemental application.

Affected firms will need to acquire some new professional skills,

since this rule deals with a new manufacturing process that will

require technicians to have a knowledge of sterility procedures,

specifically the asceptic sterilization process. Any other skills

necessary for implementation of this proposal (e.g., skills associated

with preparing the application) should already exist within the firms

and should not need to be newly acquired.

C. Minimizing the Impact on Small Entities

FDA initially considered requiring conversion to sterile procedures

to take place within 6 months of the publication of a final rule, due

to the health hazards associated with existing unsterilized inhalation

products. However, the agency is concerned that this short timeframe

would give affected firms an inadequate opportunity to implement

aseptic manufacturing processes and might force some small firms to

temporarily suspend production. Thus, this proposed rule allows 1 year

for the manufacturing conversion to take place.

Exempting small businesses from the rule is not a feasible

alternative, since all of the firms believed to still be using

nonsterile manufacturing for these products are small. A size-based

exemption would thus defeat the purpose of this proposed rule.

VI. The Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that

are subject to review by OMB under the Paperwork Reduction Act of 1995

(44 U.S.C. 3501-3520). Therefore, in accordance with 44 U.S.C.

3506(c)(2)(B) and 5 CFR part 1320, FDA is providing the following

title, description, and respondent description of the information

collection contained in this proposal, along with an estimate of the

resulting annual collection of information burden. This estimate

includes the time needed for reviewing instructions, gathering and

maintaining the data needed, and completing and reviewing the

collection of information.

With respect to the following collection of information, FDA

invites comments on: (1) Whether the proposed collection of information

is necessary for proper performance of FDA's functions, including

whether the information will have practical utility; (2) the accuracy

of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Sterility requirements for inhalation solution products.

Description: The proposal would require that all inhalation

solution products, including those currently approved, be manufactured

as sterile. Applicants will have 1 year after the date of publication

of the final rule to comply with the sterility requirement.

Description of Respondents: Drug manufacturers.

As indicated in the accompanying chart, the proposed one-time

reporting requirement would require that most firms commit about 160

additional hours per product to report the sterility information in a

supplement to a drug application (20 hours for certain manufacturers of

sterile products) and about 2 additional hours per product to document

sterility of their inhalation products.

The expected burden under the proposed rule is as follows:

Estimated Annual Reporting Burden

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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314.97 5 1 5 160 800\1\

314.70 2 1 2 20 40\2\

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\1\ Reporting burden for manufacturers of nonsterile products.

\2\ Reporting burden for manufacturers of sterile products.

Estimated Annual Recordkeeping Burden

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Recordkeepers Recordkeeping Records Recordkeeper

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211.113(b) 7 1 1 2 14

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There are no capital costs or operating and maintenance costs associated with this proposed rule.

The agency has submitted a copy of this proposed rule to OMB for

its review and approval of this information collection. Interested

persons are requested to send comments regarding this collection of

information to the Office of Information and Regulatory Affairs

(address above).

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VII. Request for Comments

Interested persons may, on or before December 22, 1997, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 200

Drugs, Prescription drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR part 200 be amended as follows:

PART 200--GENERAL

1. The authority citation for 21 CFR part 200 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508,

515, 701, 704, 705 of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 360e, 371, 374,

375).

2. New Sec. 200.51 is added to subpart C to read as follows:

Sec. 200.51 Sterility requirements for inhalation solution drug

products.

(a) All inhalation solutions for nebulization shall be manufactured

to be sterile.

(b) Manufacturers shall also comply with the recordkeeping

requirements in Sec. 211.113(b) of this chapter.

Dated: September 12, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-25130 Filed 9-22-97; 8:45 am]

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